J Crit Care 83 (2024) 154831

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Journal of Critical Care

journal homepage: www.journals.elsevier.com/journal-of-critical-care

Prevalence and prognostic relevance of invasive fungal disease during

veno-arterial ECMO: A retrospective single-center study
Jens M. Poth a, Mathias Schmandt a, Jens-Christian Schewe b, Felix Lehmann a, Stefan Kreyer a,
Zaki Kohistani c, Farhad Bakhtiary c, Gunnar Hischebeth d, Christian Putensen a,
Johannes Weller e, Stefan F. Ehrentraut a, *
a
Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, 53127 Bonn, Germany
b
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Rostock, 18057 Rostock, Germany
c
Department of Cardiac Surgery, Heart Center Bonn, University Hospital Bonn, 53127 Bonn, Germany
d
Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, 53127 Bonn, Germany
e
Department of Neurology, University Hospital Bonn, 53127 Bonn, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: To assess the prevalence and relevance of invasive fungal disease (IFD) during veno-arterial (V-A)
Aspergillosis extracorporeal membrane oxygenation (ECMO).
Candidemia Methods: Retrospective analysis from January 2013 to November 2023 of adult V-A ECMO cases at a German
Candidiasis
University Hospital. Parameters relating to IFD, demographics, length of stay (LoS), days on ECMO and me­
Extracorporeal membrane oxygenation
(ECMO)
chanical ventilation, prognostic scores and survival were assessed. Multivariable logistic regression analyses with
Invasive fungal disease (IFD) IFD and death as dependent variables were performed. Outcome was assessed after propensity score matching
Invasive fungal infection (IFI) IFD-patients to non-IFD-controls.
Veno-arterial ECMO Results: 421 patients received V-A ECMO. 392 patients with full electronic datasets were included. The preva­
lence of IFD, invasive candidiasis and probable invasive pulmonary aspergillosis was 4.6%, 3.8% and 1.0%.
Severity of acute disease, pre-existing moderate-to-severe renal disease and continuous kidney replacement
therapy were predictive of IFD. In-hospital mortality (94% (17/18) compared to 67% (252/374) in non-IFD
patients (p = 0.0156)) was predicted by female sex, SOFA score at admission, SAVE score and IFD (for IFD:
OR: 8.31; CI: 1.60–153.18; p: 0.044). There was no difference in outcome after matching IFD-cases to non-IFD-
controls.
Conclusions: IFD are detected in about one in 20 patients on V-A ECMO, indicating mortality >90%. However,
IFD do not contribute to prognosis in this population.

1. Introduction patients, antifungal treatment is complicated because the PK/PD

Extracorporeal membrane oxygenation (ECMO) is increasingly used
for support in critically ill adult patients [1]. Veno-arterial (V-A) ECMO
can provide circulatory support to patients with cardiac failure [2].
Although ECMO increases overall survival, mortality in patients treated
with V-A ECMO remains high [3,4].
ECMO is associated with life-threatening complications such as
intracranial hemorrhage, vascular injury, thrombosis, limb ischemia and
coagulopathy [3,5-8]. Nosocomial infections are also common in pa­
tients supported with ECMO [8-13]. Candida spp. are the most prevalent
pathogens in patients on long-term ECMO support [10,13]. In these
(pharmacokinetics/pharmadynamics) of most antifungals is altered. In
addition, removal or exchange of the ECMO system is not feasible
despite possible fungal contamination. Consequently, current studies
suggest a detrimental impact of invasive candidiasis (IC) on survival
under veno-venous extracorporeal membrane oxygenation (V–V
ECMO) [14,15]. Others, however, could not find a significant impact on
mortality [8,11,13,16].
Particularly in patients supported by V-A ECMO, there is a paucity of
data on the incidence and relevance of IC, ranging from 1.2% in a mixed
ECMO population [14] to 5.7% in a single-center analysis [10]. It re­
mains unclear whether IC has an impact on the survival of these patients.

* Corresponding author at: Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
E-mail address: Stefan.ehrentraut@ukbonn.de (S.F. Ehrentraut).

https://doi.org/10.1016/j.jcrc.2024.154831

Available online 25 May 2024

0883-9441/© 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-
nc/4.0/).
J.M. Poth et al.
Similarly, there is a paucity of data regarding the relevance of
invasive aspergillosis (IA) in patients on V-A ECMO.
In the present study, we present the results of a single-center retro­
spective analysis of the prevalence and prognostic impact of invasive
fungal disease (IFD) in patients receiving V-A ECMO support at our
center.
2. Methods
We reviewed all ECMO (n = 915) case data from 01/01/2013 to 11/
21/2023 from our institutional database. The local Ethics Committee
approved the analysis, and the need for individual informed consent was
waived (Bonn Medical Faculty Ethics Committee #422/23-EP).
Only patients under V-A ECMO support (n = 421) with full electronic
datasets (n = 392) were included in our study (Fig. 1). Demographics,
the Charlson Comorbidity Index (CCI) [17], the Sequential Organ Fail­
ure Assessment Score (SOFA) [18], and length of mechanical ventilation
prior to ECMO initiation were collected. General severity of disease and
nursing workload were assessed using the Simplified Acute Physiology
Score II (SAPS II) and Therapeutic Intervention Scoring System-10
(TISS-10), as described previously [15]. Parameters for the calculation
of the Survival After Veno-arterial ECMO (SAVE) score were collected.
The duration of ECMO support, total days of mechanical ventilation,
overall length of stay (LoS) in hospital, LoS in the intensive care unit
(ICU), length of survival after ECMO weaning and survival after hospital
discharge were also assessed.
All microbiological samples and tests of each study patient were
screened for molds and yeasts. For this study, a single finding of can­
didemia or recovery of Candida spp. from other sterile sites with clinical
or radiological evidence of infection defined IC [19]. In agreement with
the most recent consensus definitions, findings in tracheal aspirates,
broncho-alveolar lavage fluid (BALF), and urine were not considered as
infection [20,21]. Samples were not tested for Beta-D-glucan (BDG). In
the case of Aspergillus spp., all cultural findings in body fluids and bi­
opsies obtained from normally sterile sites using aseptic technique with
evidence of associated tissue damage were considered as IA [22,23].
Cultural findings in tracheal aspirates or BALF were classified as prob­
able invasive pulmonary aspergillosis (pIPA), if all criteria of a modified
AspICU algorithm were met [22,23]. The modifications of the AspICU
algorithm were as follows: Instead of fever and body temperature, other
indicators of infection (leukocyte counts, CRP, PCT) were used, as body
temperature is altered by the ECMO circuit. Further, “worsening respi­
ratory insufficiency” was defined as necessary increase in the fraction of
oxygen delivered to the lungs and the ECMO circuit, with the remaining
ventilator settings and ECMO settings kept constant.
Susceptibility to antifungal therapeutics was determined according
to the European Committee on Antimicrobial Susceptibility Testing
(EUCAST). Following institutional standard procedures, blood cultures
Fig. 1. Inclusion process for the selected patient cohort. ECMO: Extracorporeal Membrane Oxygenation. IFD: Invasive Fungal Disease. V-A: Veno-Arterial. V-V:
Veno-Venous.
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Journal of Critical Care 83 (2024) 154831
(BC) were routinely taken with every insertion of central lines. Further
sampling and testing of bodily fluids, tissue and secretions was per­
formed at the discretion of the treating physicians.
All values are presented as frequencies, median ± interquartile range
(IQR), or mean ± SE, as applicable. The distribution of data was assessed
for normality using the Shapiro–Wilks test. For quantitave variables,
levels of significance were determined using the Wilcoxon rank sum test.
For categorical data, the Pearson’s Chi-squared test was used to assess
between-group differences. For the multivariable logistic regression
(MVR) analysis with in-hospital mortality as dependent variable, the a
priori defined potential predictors demographics, CCI, the previously
assessed parameters of severity of disease (SOFA, SAPS II, TISS-10,
SAVE), length of mechanical ventilation prior to ECMO initiation,
duration of ECMO support and IFD were assessed by univariate analysis.
If this analysis was significant (p < 0.05), the corresponding variable
was included into the first MVR model. Variables were then excluded in
a backward manner, until the model or all remaining variables reached
statistical significance. To correct for potential differences in premorbid
conditions and initial disease severity, we utilized propensity score
matching (PSM) including the variables age, gender, BMI, CCI and SOFA
score with nearest-neighbor matching and a caliper of 0.2. Between-
group differences in outcome parameters were then analyzed as out­
lined above. For a second MVR analysis with IFD as dependent variable,
demographics, CCI (total score), pre-existing moderate-to-severe renal
disease, CKRT prior to IFD, and duration of ECMO prior to IFD were
included. Further analysis was the as for in-hospital mortality.
Using Kaplan-Meier analysis and log-rank test for trend, we
compared survival between patients with and without IFD [24]. Indi­
vidual survival time was assessed by active follow-up. Patients were
deemed at risk until proven demise or the last time of contact. In­
dividuals with no further contact, i.e. unknown survival status after last
contact, were censored at the last known time point (indicated by ver­
tical dashes in the Kaplan-Meier plots). A p-value <0.05 was considered
statistically significant.
Data were analyzed using “R 4.2.2” [25].
3. Results
Between 01/01/2013 and 11/21/2023, a total of 915 patients
received ECMO support at our center (Fig. 1). Of 421 patients receiving
V-A ECMO, 392 had complete datasets available and were included in
the analysis. Among these, 18 patients fulfilled the criteria for IFD (see
Materials and Methods), resulting in an IFD-prevalence of 4.6%. The
incidence was calculated with 6.46 cases per 1000 ECMO-days,
including patients with IFD on the day of ECMO initiation. Including
only cases with detection of IFD after initiation of ECMO, the incidence
was 4.76 per 1000 ECMO-days.
Between IFD-positive and IFD-negative patients, there were no
J.M. Poth et al. Journal of Critical Care 83 (2024) 154831

significant differences in age, sex and BMI (Table 1). Also, there was no
difference in the overall CCI, reflecting pre-existing disease before
ECMO initiation. However, the prevalence of pre-existing moderate-to-
severe renal disease, as defined by Charlson et al. [17], was higher in
patients contracting IFD during ECMO (6/18 (35%) vs. 52/372 (14%); p:
0.0279) (Suppl. Table 1). They also had higher median SOFA scores at
the day of ECMO initiation (10.0 (IQR: 9.0; 10.8) vs. 9.0 (IQR: 7.0; 11.0);
p: 0.0255), which was also reflected by higher median SAPS II values 24
h later (62.0 (IQR: 56.5; 68.0) vs. 53.0 (IQR: 45.0; 63.0); p: 0.0047).
There was no significant difference in the SAVE score, with − 8.5 (IQR:
− 12.8; − 4.0) (IFD-positive) and − 8.0 (IQR: − 11.8; − 4.0) (IFD-nega­
tive), corresponding to a predicted survival of 30% for both groups [26].
Indications for V-A ECMO were also similar between groups (Suppl.
Table 2).
Overall, weaning from ECMO was successful in 53% (206/392) of all
cases (Table 2). 69% (269/392) of patients died in hospital (survival to
discharge: 31%). The median length of survival for all patients was 15
days (IQR: 4.0; 114.2). In-hospital mortality was significantly higher in
IFD-positive patients (94% (17/18) vs. 67% (252/374); p: 0.0156), with
a trend towards a shorter median survival, as determined by Kaplan-
Meier analysis (12.5 days (CI: 7.0; 35.0) versus 16 days (CI: 13.3;
19.0); p: 0.063) (Fig. 2). In IFD-positive patients, the total median
duration of ECMO support was longer (9.5 days (IQR: 6.1; 18.2) vs. 6.0
days (IQR: 2.0; 9.0); p: 0.0123), TISS-10 values at discharge were higher
(29.5 (IQR: 26.0; 36.5) vs. 26.0 (IQR: 10.0; 31.0); p: 0.0283) and CKRT
during ECMO was required more often (94% (17/18) vs. 30% (114/
374); p: <0.00001). There were no statistically significant differences in
other documented outcome parameters.
In IFD-patients, Candida albicans represented the most frenquently
detected fungal pathogen, followed by other Candida spp. (Table 3).
Candidemia was present in all these cases, defining IC, with an preva­
lence of 3.8% (15/392). Three patients had additional evidence of
Candida infection of the mediastinum, sternum, pericardium and a left-
ventricular assist device (LVAD). In one patient with candidemia, a
central line (Shaldon catheter) was the primary site of infection. All
other cases presented primary candidemia. Aspergillus fumigatus was
detected in BALF of five patients. Four cases were classified as pIPA,
corresponding to 1.0% of all patients included in our study (4/392).
There were four cases with simultaneous detection of either two Candida
spp. or with Candida spp. and Aspergillus fumigatus. We did not detect
other molds or yeasts.
Antifungal treatment was initiated in 15 patients, the remaining
three patients died before treatment was initiated (Table 3). The median
delay between retrieval of IFD-establishing samples and start of treat­
ment was two days (IQR: 2.0; 2.5). Antifungal therapy was changed to a
second substance in four cases. In all cases, detected pathogens were
susceptible to the primary and secondary treatment. Treatment success –
as defined by negative culture results from the site of infection and
negative blood cultures, if applicable – occurred in 50% (9/18) of cases
(60% of cases receiving antifungal treatment), seven days (IQR: 3.5;
11.0) after detection. The median total duration of antifungal therapy
was seven days (IQR: 3.3; 15.2). Twelve patients died within four days
(IQR: 2.75; 14.0) with ongoing antifungal therapy. In three patients,
antifungal treatment was continued for 15 days after clearance of
infection.
Stress-dose steroids were given to 14 patients (78% of IFD-positive
patients) for a median of eight days (IQR: 4.0; 10.5) before detection
of IFD (Table 3): One patient received dexamethasone (6 mg i.v. opd),
the others hydrocortisone (10 mg/h, continuous infusion).
Prior to detection of IFD, the median time on mechanical ventilation
(MV) was eight days (n: 16; IQR: 4.5; 10.0), the median time on ECMO
was eight days (n: 13; IQR: 5.0; 10.0) and the median time on CKRT was
7.5 days (n: 12; IQR: 4.8; 12.5). In the remaining patients, IFD were
either detected before or with the initiation of the corresponding
measures.
A peripheral ECMO configuration (Vf – Af; VfVf – Af; Vf – As) was
chosen in 12 IFD-positive patients (67%). Two of these had additional
transvalvular left ventricular support (TVLS, axial pump), in one a left
ventricular vent (vntc) was established. In two patients, the thorax
remained open. Central ECMO configurations were established in the
other six patients (33%), as outlined in Table 3. The chest remained open
in five of those patients, in one the left ventricle was vented and one
received TVLS.
We performed multivariable logistic regression analysis with the
dependent variable “in-hospital mortality”, which had been significantly
higher in IFD-patients (Table 2). We included the demographic

Table 1
Characteristics of patients with Invasive Fungal Disease (IFD) and without IFD on V-A ECMO.
Variable IFD Total Significance

Negative Positive

age at admission [years] median [IQR] 64.5 [56.0;70.8] 54.8 [44.2;72.1] 64.2 [55.7;70.9] ns
N (NA) 374 (0) 18 (0) 392 (0)
weight [kg] median [IQR] 85.0 [74.0;96.0] 84.0 [71.2;97.5] 85.0 [74.0;96.0] ns
N (NA) 374 (0) 18 (0) 392 (0)
height [cm] median [IQR] 175.0 [168.0;180.0] 177.5 [167.0;183.0] 175.0 [168.0;180.0] ns
N (NA) 374 (0) 18 (0) 392 (0)
BMI median [IQR] 27.7 [24.7;30.9] 26.2 [24.6;30.0] 27.6 [24.7;30.9] ns
N (NA) 374 (0) 18 (0) 392 (0)
Sex female 102 (27%) 5 (28%) 107 (27%) ns
male 272 (73%) 13 (72%) 285 (73%)
Total 374 (95%) 18 (5%) 392 (100%)
SOFA (at day of ECMO initation) median[IQR] 9.0 [7.0;11.0] 10.0 [9.0;10.8] 9.0 [7.0;11.0] p: 0.0255
N (NA) 374 (0) 18 (0) 392 (0)
CCI median[IQR] 2.0 [1.0;3.0] 2.5 [1.0;4.0] 2.0 [1.0;3.0] ns
N (NA) 374 (0) 18 (0) 392 (0)
SAVE score median[IQR] − 8.0 [− 11.8;-4.0] − 8.5 [− 12.8;-4.0] − 8.0 [− 12.0;-4.0] ns
N (NA) 374 (0) 18 (0) 392 (0)
SAPS II (24 h after ECMO initiation) median[IQR] 53.0 [45.0;63.0] 62.0 [56.5;68.0] 54.0 [45.0;63.0] p: 0.0047
N (NA) 301 (73) 15 (3) 316 (76)
TISS-10 (24 h after ECMO initiation) median[IQR] 31.0 [26.0;38.0] 38.0 [26.5;41.5] 31.0 [26.0;38.0] ns
N (NA) 298 (76) 15 (3) 313 (79)
CPR prior to ECMO N (%) 154 (41%) 5 (29%) 159 (41%) ns
CKRT prior to ECMO N (%) 115 (31%) 7 (39%) 122 (31%) ns

BMI: Body Mass Index. CCI: Charlson Comorbidity Index. CKRT: Continuous kidney replacement therapy. CPR: Cardiopulmonary Resuscitation. ECMO: Extracorporeal
Membrane Oxygenation. IFD: Invasive Fungal Disease. IQR: Interquartile Range. NS: Not significant. SAPS II: Simplified Acute Physiology Score II. SAVE: Survival
After Veno-arterial ECMO. SOFA: Sequential Organ Failure Assessment. TISS-10: Therapeutic Intervention Scoring System-10.

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J.M. Poth et al. Journal of Critical Care 83 (2024) 154831

Table 2
Outcome of Patients with Invasive Fungal Disease (IFD) and without IFD on V-A ECMO.
Variable IFD Total Significance

Negative Positive

in-hospital death N (%) 252 (67%) 17 (94%) 269 (69%) p value: 0.0156
length of stay [days] Median [IQR] 17.8 [7.0;39.5] 18.7 [8.0;24.9] 17.8 [7.0;39.0] ns
ICU length of stay [days] Median [IQR] 15.6 [5.4;34.8] 14.2 [7.6;24.9] 15.6 [5.6;34.3] ns
days of survival Median [IQR] 15.7 [4.0;133.0] 12.5 [6.2;24.5] 15.0 [4.0;114.2] ns
N (NA) 373 (1) 18 (0) 391 (1)
Total duration of ECMO therapy [days] Median [IQR] 6.0 [2.0;9.0] 9.5 [6.1;18.2] 6.0 [2.0;9.2] p: 0.0123
N (NA) 373 (1) 18 (0) 391 (1)
successful ECMO weaning N (%) 200 (53%) 6 (33%) 206 (53%) p: 0.0946
Days on mech. Ventilation total Median [IQR] 13.0 [5.0;30.0] 13.5 [9.2;25.8] 13.0 [5.0;30.0] ns
N (NA) 373 (1) 18 (0) 391 (1)
SAPS II at ICU discharge Median [IQR] 51.5 [35.0;63.2] 58.0 [49.8;60.0] 52.0 [36.2;63.0] ns
N (NA) 252 (122) 14 (4) 266 (126)
TISS-10 at ICU discharge Median [IQR] 26.0 [10.0;31.0] 29.5 [26.0;36.5] 26.0 [10.0;32.0] p: 0.0283
N (NA) 253 (121) 14 (4) 267 (125)
CKRT during ECMO N (%) 114 (30%) 17 (94%) 125 (32%) p: <0.00001

CKRT: Continuous Kidney Replacement Therapy. ECMO: Extracorporeal Membrane Oxygenation. ICU: Intensive Care Unit. IQR: Interquartile Range. SAPS II:
Simplified Acute Physiology Score II. SOFA: Sequential Organ Failure Assessment. TISS-10: Therapeutic Intervention Scoring System-10.

Fig. 2. Long-term Survival of Patients on V-A ECMO (Kaplan-Meier Analysis). IFD: Invasive Fungal Disease. Vertical dashes indicate censoring (i.e. last known time
of survival).

parameters age, sex and BMI, parameters of disease severity (SOFA score
and SAVE score), and detection of IFD during ECMO. In this analysis,
male sex (OR 0.58; CI: 0.34–0.97; p: 0.044), SOFA score (OR 1.15; CI:
1.05–1.26; p: 0.003), SAVE score (OR 0.91; CI: 0.86–0.96; p: <0.001)
and IFD (OR 8.31; CI: 1.60–153.18 p: 0.044) predicted in-hospital
mortality (Fig. 3).
Utilizing PSM, 18 IFD-positive patients were successfully matched to
18 IFD-negative controls based on the treatment-independent parame­
ters age, gender, BMI, CCI and SOFA score at admission. Between-group
differences were then re-analyzed as for the unmatched groups: There
were no statistically significant differences in CCI items or in other pre-
existing immunocompromising conditions (Suppl. Table 3). There were
no statistically significant differences in outcome parameters between
the matched groups, including in-hospital mortality (Suppl. Table 4).
Similarly, there was no statistically significant difference in overall
survival as determined by Kaplan-Meier analysis (Suppl. Fig. 1).
Further, we performed multivariable logistic regression analysis to
identify risk factors for IFD, as described in the “Methods” section. Since

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J.M. Poth et al. Journal of Critical Care 83 (2024) 154831

Table 3 initiation (OR 1.06; CI: 1.01–1.12; p: 0.029), and CKRT prior to IFD (OR:
Detected fungal pathogens and treatment characteristics in patients on V-A 3.61; CI: 1.08–13.24; p: 0.042) proved to be significant predictors of IFD
ECMO. on V-A ECMO (Fig. 4).
Fungi and antifungal treatment:

Detected fungal C. albicans 6 (1 co-infection with 4. Discussion

pathogen (n (in % of C. dubliniensis (33%) C. parapsilosis, 1 co-
IFD-patients)) C. glabrata 2 infection / 1 colonization In our retrospective, single-center study in patients on V-A ECMO for
C. krusei (11%) with Asp. fumigatus)(1 co- circulatory support, we observed an prevalence of IFD of 4.6%. Multi­
C. parapsilosis 5 infection with C. tropicalis)
variable logistic regression analysis identified a higher disease severity
C. tropicalis (28%) (1 co-infection with
Asp. fumigatus 1 (6%) C. albicans) (higher SAPS II values) and CKRT prior to IFD as independent predictors
2 (1 co-infection with C. (Fig. 4). Detection of IFD was associated with an increased mortality of
(11%) dubliniensis) >90% (Table 2 and Fig. 3). Candida spp. were detected in 83% of IFD
1 (6%) (4 classified pIPA, plus 1
cases (prevalence 3.8%, 15/392), Aspergillus fumigatus in 28%, with
5 additional colonization, 2
(28%) co-infections with
classification as pIPA in 22% of IFD cases (prevalence 1.0%, 4/392)
C. albicans) (Table 3).
1st Antifungal Anidulafungin 1 Survival to discharge was 31%, which was similar to the predicted
Caspofungin 11 (1 simultaneous treatment survival rate (30%) associated with the median SAVE score of the cohort
Fluconazol 1 with voriconazol)
(− 8.0) [26]. This is in line with other observations: A recent meta-
Voriconazol 3 (1 simultaneous treatment
None 3 with caspofungin) analysis demonstrated a one-year survival of 36.7% in patients on V-A
2nd Antifungal Amphotericin B 2 ECMO for cardiogenic shock [27], which is similar to other regional
(lipo.) 1 studies [1,4].
Caspofungin 1
The prevalence of candidemia was 3.8% in our study. Several other
Voriconazol
Treatment success 9 As defined by negative
studies reported Candida spp. as one of the most frequent causative
(50%) culture from same site pathogen of blood stream infections in V-A ECMO patients
Time to treatment 2 [2.0; [8,9,11,13,28]. Lee et al. observed a prevalence of candidemia between
after sampling 2.5] 3.3% (8/244, only V-A ECMO) and 4.3% (15/350, V-A ECMO and veno-
(median in days
arteriovenous (V-AV) ECMO) [29]. Kim et al. identified 11 cases of
[IQR])
Time to treatment 7.0 candidemia in 194 patients on V-A ECMO (prevalence: 5.7%) [10]. In a
success (median in [3.5; Spanish study of non-ECMO ICU-patients with a LoS of at least seven
days [IQR]) 11.0] days, the prevalence of proven IC was 5.5% and candidemia was
Duration of therapy (in all treated 7.0 detected in 3.3% of patients with systematic sampling [30]. In our study,
(median in days patients) [3.3;
[IQR]) 15.2]
sampling was performed at the discretion of the treating physician and
with every insertion of indwelling catheters. Therefore, the observed
prevalence is probably underestimating the true prevalence of IC. IC
Parameters of organ support:
Duration of stress-dose 8.0 N = 14 (78%) comprises primary candidemia, deep-seated candidiasis with secondary
steroids before IFD* [4.0; candidemia and deep-seated candidiasis without candidemia [20,31]: It
(median in days 10.5] is conceivable that some cases of deep-seated without candidemia were
[IQR]) missed, due to the impracticality of repeated CT studies and tissue bi­
Duration of MV before 8.0 N = 16 (89%)
IFD* (median in [4.5;
opsies in our study population. For the same reason, the true prevalence
days [IQR]) 10.0] of candidemia in ECMO-patients is probably higher than reported by a
Time on ECMO before 8.0 N = 13 (72%) recent ELSO (Extracorporeal Life Support Organization) registry anal­
IFD* (median in [5.0; ysis (1.2%) [14]. This analysis included a mixed cohort of patients on
days [IQR]) 10.0]
either V–V ECMO or V-A ECMO. In the same analysis, the prevalence of
Duration of CKRT 7.5 N = 12 (67%)
before IFD* (median [4.8; aspergillus involvement was reported with 1.4% [14], nearly identical to
in days [IQR]) 12.5] our observation (1.0%). Of note, the definitions of invasive aspergillosis
V-A ECMO Vf – A f 6 TVLS: 1 vary between studies, and do not always meet criteria for proven,
cannulation** VfVf – Af 1 open chest: 1 probable or putative diagnosis of invasive aspergillosis according to
Vf – A s 5 TVLS: 1; open chest: 1;
Vf – Ao 2 vntc: 1
current guidelines [19,21,23,32,33]. In our study, no patient with
VfVj – Ao 1 open chest: 2 samples positive for aspergillus met the criteria for proven invasive dis­
RA – Ao 3 vntc: 1 ease, as defined by the European Organization for Research and Treat­
TVLS: 1; open chest: 3 ment of Cancer (EORTC) and the Mycoses Study Group Education and
Asp.: Aspergillus. C.: Candida. CKRT: Continuous Kidney Replacement Therapy. Research Consortium (MSGERC) [21]. However, four patients with
ECMO: Extracorporeal Membrane Oxygenation. IFD: Invasive Fungal Disease. pulmonary aspergillus involvement met the AspICU criteria for pIPA
IQR: Interquartile Range. MV: Mechanical Ventilation. pIPA: Probable Invasive [22,23]. One of these patients was also under long-term immunosup­
Pulmonary Aspergillosis. *Only patients on steroids/MV/ECMO prior to detec­ pressive therapy (one case with myasthenia gravis and chronic
tion of IFD considered. **ECMO cannulation: Af: femoral artery. Ao: ascending lymphatic leukemia), also meeting the EORTC/MSGERC-2019 pIPA
aorta. As: subclavian/axillary artery. RA: right atrium. TVLS: transvalvular left criteria [21]. Two patients suffered from viral pneumonia, so these cases
ventricular support (axial pump). Vf: femoral vein. Vj: internal jugular vein. vntc: also met the ICU Working Group criteria published in 2021 [19]. One
Venting left cardiac ventricle.
patient had overt acute liver failure on admission, not quite fulfilling the
most recently published FUNDICU (Invasive Fungal Diseases in Adult
pre-existing moderate-to-severe renal disease was more prevalent in IFD Patients in ICU) criteria [32]. All of these patients were under stress-dose
patients, it was also included. To investigate whether CKRT was a risk steroids for several days before detection of aspergillus.
factor for IFD, the variable “CKRT prior to IFD”, i.e. CKRT before Others report an increased risk of infectious complications with V-A
detection of IFD (Table 3), was also included. Similarly, we also included ECMO compared to V–V ECMO [28]. We, however, observed a very
days at risk on ECMO, that is the duration of ECMO before an IFD was similar prevalence (4.8% - 5.98% in V–V ECMO patients at our center)
detected (see also Table 3). In this analysis, the SAPS II 24 h after ECMO [15,34]. In contrast to patients on V-A ECMO, pre-existing severe renal

5
J.M. Poth et al. Journal of Critical Care 83 (2024) 154831

Fig. 3. Forest Plot: Multivariable Analysis of Risk Factors for In-Hospital Mortality in Patients on V-A ECMO. BMI: Body Mass Index. IFD: Invasive Fungal Disease.
SAVE: Survival After Veno-arterial ECMO. SOFA: Sequential Organ Failure Assessment. The dots and bars represent odds ratios with confidence intervals, respec­
tively. *: p < 0.05.

6
J.M. Poth et al.
Fig. 4. Forest Plot: Multivariable Analysis of Risk Factors for IFD in Patients on V-A ECMO. CKRT: Continuous Kidney Replacement Therapy. ECMO: Extracorporeal
Membrane Oxygenation. SAPS II: Simplified Acute Physiology Score II. SAVE: Survival After Veno-arterial ECMO. SOFA: Sequential Organ Failure Assessment. The
dots and bars represent odds ratios with confidence intervals, respectively. *: p < 0.05; #: p < 0.1.
disease was less frequent in our patient cohort on V–V ECMO [34].
However, other pre-disposing factors, such as influenza infection
[35–38] or COVID-19 [39–48], were more frequent, which could
explain the resulting similar prevalence of IFD in our cohorts.
We identified the severity of acute disease, as reflected by higher
initial SAPS II scores, as an independent predictor of IFD. Similarly,
Aubron et al. reported the pre-ECMO SOFA score to be an independent
risk factor for blood stream infections with any pathogen [9]. Also in
critically ill patients not on ECMO, a higher APACHE II (Acute Physi­
ology and Chronic Health Evaluation II) score on admission, also
reflecting severity of acute disease, proved to be an independent risk
factor for IC [49,50].
Several previous studies demonstrated a significant association be­
tween nosocomial infections and longer ECMO runs, as reviewed by Biffi
et al. [28] Likewise, Lee et al. found total ECMO duration to be an in­
dependent risk factor for candidemia [29]. While we also found an as­
sociation of total ECMO duration and IFD (Table 2), the duration of
ECMO was not a predictor for IFD (Fig. 4). Of note, in IFD-patients, we
only considered the duration of ECMO prior to the detection of fungi. We
conclude that IFD might have contributed to longer ECMO runs in our
patients, but that ECMO itself did not increase the risk for IFD.
Renal failure is also a recognized risk factor for IC [51,52]. In line
with a previous report [14], we confirmed pre-existing moderate-to-
severe renal disease and CKRT to be predictive for IFD, while pre-
existing moderate-to-severe renal disease did not reach statistical sig­
nificance (Fig. 4).
7
Journal of Critical Care 83 (2024) 154831
We report for the first time that detection of IFD in patients on V-A
ECMO indicates a striking increase in mortality. In contrast, Aubron
et al. report blood stream infections not to be an independent risk factor
for mortality. In their studies, however, bacterial and fungal pathogens
were combined and not considered separately [8,9]. Two other studies
in mixed cohorts of patients on V–V and V-A ECMO report a higher
mortality for patients with IFD [14,29]. We focused only on patients on
V-A ECMO for circulatory support: In our cohort, the detection of IFD
was associated with an increase in mortality from 67% to 94%. This is
despite the fact that antifungal treatment success was observed in 50%
of the cases (Table 3). To further investigate this observation, we per­
formed a multivariable regression analysis with a priori defined vari­
ables: We also included externally validated scores used to predict
mortality in the general ICU population, in cardiac surgery patients and
in V-A ECMO patients [26,53–58]. We also included age, gender and
BMI, as these parameters were shown to impact on survival in critically
ill patients receiving V-A ECMO [59–62]. IFD predicted in-hospital
mortality (OR 8.31; CI: 1.60–153.18 p: 0.044) (Fig. 3). Further inde­
pendent predictors were the SOFA score and the SAVE score, reflecting
the severity of disease pre-ECMO. Of note, female sex was also associ­
ated with lower survival. Further studies are needed to further explore
this finding.
To further explore the contribution of IFD to mortality, we utilized
PSM to match IFD-positive patients to IFD-negative controls according
to age, gender, BMI, premorbid state (CCI) and initial severity of disease
(SOFA score). Subsequent analysis did not demonstrate any difference in
J.M. Poth et al.
mortality after matching. Hence, we conclude that IFD indicate prog­
nosis quoad vitam. However, there is no evidence showing a contribution
of IFD to mortality in our relatively small cohort of matched patients.
Based on our data, IFD should be regarded as indicators of a dire
prognosis, associated with, but not causing, death. This is supported by
the fact, that apparent clearance of infection was achieved in 50% of IFD
cases.
We provide a detailed analysis of antifungal treatment in IFD pa­
tients on V-A ECMO: Echinocandins were used in twelve patients (66%),
triazoles in four patients. Of note, standardized antifungal prophylaxis
was not performed at our institution during the study period, irre­
spective of open chest treatment. In most cases, treatment was initiated
before validated test results were available (i. e. empirically), and all
fungal pathogens were susceptible to the chosen treatment regimen.
Since ECMO cannulae cannot usually be exchanged, we suggest treat­
ment according to current guidelines for candidemia with non-
removable catheters [20,63,64]: Candida spp. grown in biofilms are
resistant to fluconazole and voriconazole, but remain susceptible to
echinocandins and amphotericin B lipid formulations [65–67]. Hence,
the latter agents should be used. For the treatment of IA, current
guidelines recommend voriconazole [33,68]. However, in our experi­
ence, reaching sufficient plasma levels of voriconazole in ECMO patients
is challenging. As the PK/PD of most antifungals is altered during ECMO,
we strongly recommend therapeutic drug monitoring when available
[31].
Our study is limited by the number of cases and its retrospective,
single-center design. Another limitation is the definition of IFD: For IC,
current definitions of proven disease are met [20,32]. It is conceivable
that some cases of deep-seated without candidemia were missed. In
contrast, no patient with aspergillus involvement met the criteria for
proven invasive disease, as defined by the EORTC/MSGERC [21]. Only
four patients with pIPA according to AspICU criteria were identified.
Also, screening for IFD occurred mostly at the discretion of the treating
physician, probably leading to underestimation of the true IFD inci­
dence. Lastly, many known risk factors for IFD were not included in our
multivariable analysis.
Most patients in our study did not present classical risk factors for
IFD, such as malignancies or long-term immunosuppressive therapy.
Based on our results, we believe that critical illness requiring V-A ECMO
should be regarded as significant risk factor for IFD. We demonstrate for
the first time, that IFD predict a detrimental prognosis in this popula­
tion. Hence, systematic sampling seems prudent and larger future
studies should address a potential contribution of IFD to mortality and
the role of pre-emptive antifungal therapy.
5. Conclusion
In summary, we demonstrate for the first time that the detection of
IFD indicates a striking increase in mortality in patients on V-A ECMO.
We conclude that IFD can be utilized for outcome prediction and that
screening protocols should be established. Future studies need to
investigate whether IFD also contribute to mortality this population.
Institutional review board approval
The analysis was approved by the local Ethics Committee and the
need for individual informed consent was waived (Bonn Medical Faculty
Ethics Committee #422/23-EP).
Disclosures
All authors have nothing to disclose.
Funding
This research received no external funding.
8
Journal of Critical Care 83 (2024) 154831
CRediT authorship contribution statement
Jens M. Poth: Writing – review & editing, Writing – original draft,
Visualization, Methodology, Investigation, Formal analysis, Data cura­
tion, Conceptualization. Mathias Schmandt: Writing – original draft,
Visualization, Investigation, Data curation. Jens-Christian Schewe:
Writing – review & editing, Supervision. Felix Lehmann: Writing –
review & editing, Investigation. Zaki Kohistani: Writing – review &
editing, Investigation. Farhad Bakhtiary: Writing – review & editing.
Gunnar Hischebeth: Writing – review & editing, Methodology, Data
curation. Christian Putensen: Writing – review & editing, Supervision,
Resources. Johannes Weller: Writing – review & editing, Writing –
original draft, Methodology, Formal analysis. Stefan F. Ehrentraut:
Writing – review & editing, Writing – original draft, Visualization, Su­
pervision, Project administration, Methodology, Investigation, Formal
analysis, Data curation, Conceptualization.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jcrc.2024.154831.
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cid/ciw326. RA: right atrium
SAPS: Simplified Acute Physiology Score
SAVE score: Survival After Veno-arterial ECMO score
Glossary SOFA score: Sequential Organ Failure Assessment score
Spp.: Subspecies
TISS-10: Therapeutic Intevention Scoring System-10
Af: femoral artery
TVLS: transvalvular left ventricular support (axial pump)
Ao: ascending aorta.
V-A ECMO: Veno-arterial ECMO
APACHE II: Acute Physiology and Chronic Health Evaluation II
V-AV ECMO: Veno-arteriovenous ECMO
As: subclavian/axillary artery
Vf: femoral vein
Asp.: Aspergillus
Vj: internal jugular vein
BALF: Bronchoalveolar lavage fluid
Vntc: Venting left cardiac ventricle.
BC: Blood culture
V-V ECMO: Veno-venous ECMO
BMI: Body Mass Index

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